Impotence or erectile dysfunction (ED) is a problem that most men will face at some time in their life. In fact, by the time a man reaches 50 years of age, he has about a 1 in 2 chance of having some problem with his erection. The problem could be either attaining and/or maintaining his erection long enough to complete the sexual act. As men get older, the chance of getting ED increases such that a 60 year old man has approximately a 60% chance of having ED, a 70 year old man has about a 70% chance, etc. Even men in their 40's have about a 40% chance of having some form of ED, while it has been extrapolated that men in their 30's and 20's have about a 30% and 20% chance, respectively, of having noticed that something has changed with their erectile function.
From an anthropological or evolutionary standpoint, the demand on the reproductive organs inclusive of erectile function decreases after men pass their peak reproductive age which ranges from their late teens into their 20's. The actual age of onset of ED in an individual depends on many factors, such as genetics, health, lifestyle, etc. The major reason ED manifests itself, regardless of the age of onset, is due to an alteration in the corporal cavernosal smooth muscle (CSM), which is located within the cavernosal or corporal bodies of the penis.
The function of the CSM in the erectile process is to receive and trap blood entering the corporal bodies. This is accomplished when the CSM undergoes relaxation that allows it to open up and create spaces or sinusoids into which the entering blood pools. The pooling of this blood in sinusoidal spaces increases the pressure within the corporal bodies and when a certain intracorporeal pressure is reached, the pressure closes off the veins that drain the blood out of the corporal bodies, essentially trapping it within the corporal bodies. Clinically, this is how the CSM tissue is able to attain (by creating spaces for the blood to pool into) and maintain (by closing off the veins) an erection. It is when this CSM begins to degrade in some way or another and becomes incapable of either relaxing sufficiently enough to create these spaces where the blood is normally trapped or it cannot maintain its relaxation long enough so that it fails to compress the veins that provide egress for blood from the corporal bodies that ED begins to be manifested. While some men may not notice signs of ED until later in life, it is inevitable that ED will occur if one lives long enough.
There are multiple biochemical pathways involved in penile erection and dysfunction. Without stimulation, flaccidity can be considered as the baseline state. Flaccidity is due to corpus cavernosum smooth-muscle cells (“CSM”) being contracted and helicine arterioles being sufficiently contracted to limit blood flow to corpus covernosal sinuses; the sympathetic nervous system and tonic adrenergic discharge maintain baseline contraction of smooth muscle cells and arteriole blood supply (e.g., adrenergic, cholinergic, and nonadrenergic-noncholinergic pathways). So, a combination of metabolic pathways are involved in inducing the erectile processes involving smooth muscle relaxation, arterial dilation, and venous occlusion.
As noted above, by age 50 about one half of all men will have noticeable ED. The presence of certain diseases, e.g. diabetes, or certain lifestyles, e.g. smoking, may accelerate in time the genetically predetermined onset of the degradation of the CSM such that men with diabetes tend to get ED at a younger age when compared to non-diabetics. It is believed that the degradation of the CSM is ultimately the result of oxidative stress; this oxidation process within the CSM is accelerated by certain diseases (e.g. diabetes), and lifestyles (e.g. smoking), etc. Oxidation of this tissue ultimately results in a progressive loss of the CSM cells and a corresponding increase in collagen fibers or fibrous tissue. At a certain level of loss of the CSM within the corporal tissue, which some estimate to be between 10 and 20% of the CSM cells, the impact on erectile function becomes noticeable. The first recognition that one's erectile mechanism is worsening is the increase in time that it takes for one to achieve subsequent erections. This time in between subsequent erections is called the refractory period and it is the first indication that the CSM tissue is changing for the worse.
When the CSM cells begin to undergo oxidation and deteriorate either as a result of aging or some other cause, the CSM begin to induce an enzyme called inducible nitric oxide synthase (iNOS) which produces nitric oxide in high quantities within the cells that begins to combat the oxidative stress. This induction of nitric oxide (NO) by iNOS is different from the NO that is found in the nerves of the body including the nerves that innervates the CSM cells. This NO in the nerves is produced by a related enzyme, neuronal nitric oxide synthase (“nNOS”), and in the penis it only releases NO when the patient is sexually stimulated. This NO from nNOS is the major chemical that is involved in the relaxation of the CSM cells and hence is required for the initiation and maintenance of a normal erection. Therefore, while nNOS is normally present in the nerves innervating the penis, iNOS is normally not present in the CSM cells of the penis and is only induced by the CSM cells themselves when the cells experience oxidative stress. However, when iNOS is induced as seen in U.S. Pat. No. 5,594,032, human erectile dysfunction can be ameliorated by treatment with iNOS, inducers of iNOS or iNOS cDNA. Further background on sexual dysfunction, urogenital disease, ED and treatments therefore can be found in U.S. Pat. Nos. 6,133,281, 6,007,824, U.S. Patent Publication 2005/0085486, and Schwartz, Eric, et al., “Sildenafil Preserves Intracorporeal Smooth Muscle After Radical Retropubic Prostatectomy,” The Journal of Urology, Vol 171, pp. 771-774, February 2004.
With reference to U.S. Patent Publication 2005/0085486, fibrotic disease is linked to reproductive disorders and cardiovascular disease, which are both prevalent in aging males. The ubiquitous and long felt need to treat sexual dysfunction has led to surgical and pharmacological treatment approaches. The ongoing commercial success of prescription medications under the trademarks VIAGRA®, LEVITRA® and CIALIS® for treatment of ED demonstrates the long felt and widespread need for effective treatments for ED, particularly for patients that present with ED symptoms advanced sufficiently that erections of satisfactory duration at the desired time can only be reliably accomplished by taking the prescription drug.
Thus, there remains a ubiquitous and long-felt need to treat ED before it progresses to the point where pharmacological and/or other medical intervention is required in order to have desired sexual performance. Nevertheless, current ED drugs, such as VIAGRA® and CIALIS®, are generally prescribed only after the patient has presented with symptoms of ED. These drugs belong to a class of drugs called Type 5 phosphodiesterase (PDE5) inhibitors. PDE5 is an enzyme that breaks down cGMP once it is formed and PDE5 inhibitors like Viagra, Clalis and Levitra prevent the cGMP from breaking down so the effect of the cGMP on the tissues is enhanced. With regards to erectile function, cGMP is formed within the CSM from a reaction that is initiated by the NO that is released from the cavernosal nerve following sexual stimulation. The NO that begins the erectile response comes from the enzyme nNOS that is located in the nerve endings. The NO enters the CSM cells and causes a reaction to occur. NO activates the enzyme soluble guanylyl cyclase (sGC) in the cytoplasm of the CSM and this enzyme in turn converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). An increase in cGMP stimulates protein kinase G to phosphorylate potassium and calcium channels causing a decrease in cytosolic calcium, dilation of the helicine arterioles, and the relaxation of the trebecular smooth muscle where all the CSM cells are located. As noted above, the relaxation of the smooth muscle leads to an increase in the intracavernosal volume, initiating the erectile process. Normally, endogenous PDE5 enzyme degrades cGMP which reverses the relaxation of the smooth muscle cells, and leads to loss of erection whereas the ingestion of these PDE5 inhibitors prior to sexual stimulation prevent the degradation of the cGMP that is formed thereby prolonging any CSM relaxation and enhancing any erectile response.
Currently, one suffering from ED needs to see a doctor and get a prescription for an ED treatment in advance in order to be prepared for a satisfying experience. Onset and duration of the effects of PDE5 inhibitors like Viagra, Clalis and Levitra depend on the specificity of the compound. While PDE5 inhibitors are considered the “first line treatment of ED,” there are notable side effects (headache, flushing, dyspepsia, rhinitis, visual disturbances, back pain, etc.) and adverse interactions that can limit or bar their use (e.g., patients taking nitrates with a PDE5i can experience hypotension and syncope. See Dorsey, Philip et al., “Phosphodiesterase type 5 (PDE5) inhibitors for the treatment of erectile dysfunction,” Expert Opinion, Pharmacother. (2010), 11(7): pp 1109-1122). Since most men will at some time in their life get ED mainly as the result of CSM deterioration secondary to the aging process, the present inventor faced the problem of whether or not it is desirable to treat men who are asymptomatic but whose refractory period has begun to increase—a subtle sign that the CSM is beginning to undergo deterioration—in order to slow or prevent the progression of this deterioration and the forthcoming ED. For patients who already have noticeable ED symptoms, it may also be desirable to slow if not stop or reverse the progression of the ED.
Prior research indicated that high doses of ginger combined with the iNOS stimulant lipopolysaccharide (LPS) could increase nitric oxide production. However, this conflicted with other work that indicates that ginger by itself and without LPS stimulated iNOS production in a dose dependent manner and in much lower doses (see American Journal of Chinese Medicine, Vol. 32, No. 5, pp 727-735, 2004). Use of high dosages of ginger are impractical for long term routine administration, so initially the present inventor focused on isolating specific compounds within ginger, such as 6-gingerol, that might be utilized in a formulation for stimulating iNOS. However, use of such specific compounds is more expensive, and ginger by itself was insufficient to provide a reasonable alternative to PDE5 inhibitors to treat and/or prevent ED.
Numerous natural products, such as ginseng, are claimed to have “tonic” or “adaptogenic” properties. A tonic or adaptogenic effect is characterized as a general feeling of vigor or well-being that is purportedly the result of taking natural herbs, such as ginseng, ginko balboa, etc. Traditional Chinese folk medicine includes numerous teachings of herbal formulations having different purported properties. However, natural herbs are often complex mixtures, and have different names and chemical formulations depending on the geographic source. The mixture of the main or named ingredient with other ingredients and conflicting reports of the effects of same requires that careful scientific studies be conducted to determine the properties of each ingredients in an herb on specific aspects of health. The use of natural herbs in treating disease cannot be reliably predicted on the basis of folk lore.
For example, Withania somnifera, a plant in the Solanaceae or nightshade family, is also known as Ashwaganda, Indian ginseng, Amukkara in Tamil, etc. Ginseng or Ashwagandha is widely promoted for a wide variety of uses, including as an aphrodisiac or for increasing male sexual performance, alone or in combination with other ingredients. in Japanese patent application 2002-193826, to Kosuke, a combination of 1 gram of ashwaganda with 1 gram arginine or of 1 gram of ashwaganda and 1 gram of oat extract is taught as a tonic or adaptogenic composition that can increase erectile function; with daily use for 90 days, increases in sperm count and erections were reported. The essential ingredient taught by Kosuke to improve erectile function is ginseng (or Ashwaghandha). One formulation of Kosuke includes ashwagandha, arginine, and yeast with zinc; the zinc is purported to help increase sperm count. In addition to ashwagandha and/or oat, Kosuke suggests addition of at least one of eight other natural products: velvet bean, cola, guarana, ginko leaves, kava kava, maca, ginger and extracts thereof for different purposes. For example, ginger is a suggested additional ingredient for “stimulating the central nerve and thereby having a perspiration action and a blood flow stimulation action.” However, ginger is also taught by the prior art to adversely effect the nitric oxide metabolism involved in erectile function; see Liao, Hui et al., “Elucidation of Danzhixiaoyao Wan and its Constituent Herbs on Antioxidant Activity and Inhibition of Nitric Oxide Production,” eCam, Advanced Access publication Jan. 9, 2007), i.e., ginger is taught to cause, not treat, erectile dysfunction. Thus, one would not be led to add ginger to Kosuke's formulation that requires ginseng and that purports to increase erectile function in view of other teachings that ginger has an adverse effect on erectile function; such reports of ginger's adverse effect on erectile function would not outweigh Kosuke's suggestion to use ginger for a generalized tonic effect, not erectile function.
The listing of a wide variety of different compositions of natural products with unverified benefits, such as by Kosuke, can be risky to persons taking them. Sometimes one herb ingredient counteracts another, the formulation does not result in the claimed benefit, and/or in some instances medical conditions can be overlooked or made worse.
With respect to ginseng, its purported effect on sexual function may be due to impact on nitric oxide production, while arginine is also believed to play a role in endogenous nitric oxide metabolism. Nevertheless, ashwagandha or ginseng has not proven to have a sufficient benefit in the treatment of erectile dysfunction. Further, complex formulations including ginseng and a “shotgun” approach to adding up to eight different ingredients (or more) for purported enhancement of a tonic effect is not a reliable indicator that any product, natural or synthetic, has a beneficial impact on the patient or particular symptom being treated. Moreover, a tonic benefit may arise from the patient having increased food intake as a result of taking the compositions, and therefore the recipient may simply have more energy or good health resulting from caloric, vitamin and protein ingestion from their overall diet. The addition of various other ingredients without having reliable data on which ingredients have the purported benefit, while other ingredients may have their effects covered up or misinterpreted, makes it practically impossible to medically rely on generalized suggestions. Kosuke gives examples of tests with formulations that contain ashwagandha and arginine, but formulations with other ingredients were not tested for the purported effects they would bring. While the prior art suggests that ginseng may enhance erectile function, the benefits thereof have not been sufficient to replace treatment with existing erectile dysfunction drugs, such as PDE5 inhibitors, particularly for patients that are showing increases in the refractory period between erections and other symptoms indicative of progressive erectile dysfunction.
The science behind the use of dietary supplements to treat diseases has increased over the past several decades. This includes the use of natural foods or products in combination with specific compounds. For example, arginine and other amino acids have been known for decades to play important roles in biological function of humans and animals in general, however, the biological and biochemical roles are still being elucidated so that significant unpredictability remains for even small changes in formulations and/or depending on varying patient specific factors. Ginger and other herbs are often combined in foods. A combination of rosemary with other ingredients (e.g., curcumin and guercitin) is taught in U.S. Patent application 2002/0051826 to Darland et al for use in treating inflammation-related diseases. In addition to those main ingredients, Darland also suggests optionally using limonene, which can come from D-limonene or hesperidin, or the use of between 180 mg and 220 mg of ginger; the formulation can optionally include 180 mg to 220 mg of citrulline and other vitamins. Such reports indicate the safety of ingredients such as ginger, citrulline and arginine as long-term dietary supplements. While, such complex formulations are indicated to have general health benefits, there is a need for increased testing of specific formulations and determination of their impacts, both positive and negative, on different aspects of health.
Thus, there remains substantial unpredictability in the benefits and detriments of natural herbs, with a wide range of conflicting and unreliable teachings, many based on anecdotal reports that cannot be reliably reproduced. In order to make a medical treatment recommendation, one of ordinary skill in the art of Western medical research, requires data from studies that used accepted scientific methods. Such scientific methods include controls (e.g., placebo or base line formulations), independent objective analysis, patient histories and patient monitoring before, during and after each study, where possible double blind clinical trials, and uniform compositions with reliable and consistent ingredients and analyses. Otherwise, the data or conclusions are subject to criticism as subjective, anecdotal, and/or wrong based on properly conducted studies, for example studies of the type accepted by the U.S. Food and Drug Agency (US FDA), which may include an IRB protocol (Institutional Review Board protocol submitted to and approved by other scientists). It is desired to have study results that can be relied upon by clinicians trained in modern medicine and science in the United States, Europe, Canada, China, Japan, and other countries. While it is desirable to use natural products that have well-established safety as foods in place of synthetic chemical pharmaceutical formulations, such use must be based on sufficient studies to justify replacing or supplementing medicines that have met regulatory and scientific scrutiny. The present inventor was challenged by the problems of finding compositions and methods for treatment and inhibition of ED that are practical for long term routine administration, while avoiding side effects of existing formulations, enable treatment of and prevention of ED in patients that cannot utilize prior art ED treatments, and/or provide new practical and cost effective compositions to prevent as well as treat ED. Preferably, such formulations are simpler and do not include ginseng, rosemary and/or ingredients that have not been demonstrated to have a sufficient and consistent clinical benefit for the treatment of ED.